This Independent Scientist Award (K02) application proposes an integrated research eve development plan and project that includes funded experiments to further investigate glucose- and insulin- induced improvements in memory performance in aging patients with schizophrenia (RO1 MH53363), and extends this to include the investigation of N-methyl-D-aspartate (NMDA) glutamate receptor regulation of memory performance. Impairment in memory performance in schizophrenia predicts poor functional outcomes with more costly care requirements. There are currently no specific treatments for such impairment and the neurobiology that could guide treatment development remains incompletely understood. The candidate's prior research has combined the perspectives of cognitive neuroscience and neuroendocrinology into a focus on the cognitive effects of neurohormones that regulate intraneuronal energy availability, producing evidence of memory impairment by glucocorticoids and clinically significant improvements using both glucose and insulin, supporting immediate aims to define the dose-response relationships of glucose and insulin to memory performance in older patients with schizophrenia. Glucose and insulin can regulate NMDA glutamate receptor-related functions, including long-term potentiation (LTP). These reports, recent evidence for NMDA glutamate receptor hypofunction (NRH) in schizophrenia, and the importance of LTP for the study of memory, have motivated the development of-a model of memory impairment, in schizophrenia using ketamine-induced NRH in healthy humans. This KO2 Award will provide specific additional training needed to extend this by testing a rational series of pharmacological strategies to reverse memory impairment induced by NRH, including insulin, a muscarinic cholinergic receptor antagonist, a GABAa receptor facilitator, an alpha 2 adrenergic receptor agonist, a serotonergic receptor ligand, and a novel antipsychotic. All experiments utilize within subjects, placebo controlled, randomized study designs, to test the effects of treatments on cognitive performance. The goals and development activities described m this application are facilitated by the candidate's access to extensive resources including appropriate experts in preclinical and clinical cognitive neuroscience. This Award will facilitate the long-term public health goal of characterizing those fundamental neurochemical regulators of memory performance most likely to lead to therapies to treat and/or prevent cognitive impairment in aging patients with schizophrenia.